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Hamidreza Moein, Maria J Lopez, Deshea L Harris, Pedram Hamrah; Mucosal Addressin Cell Adhesion Molecule (MAdCAM)-1 Mediate Dendritic Cell Trafficking In Vivo and is Up-Regulated after Corneal Graft Rejection. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4033.
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MAdCAM-1 and vascular cell adhesion molecule (VCAM)-1 are cell adhesion molecules (CAMs), involved in trafficking of leukocytes (including conventional dendritic cells [cDCs]) to peripheral tissues. cDCs are professional antigen-presenting cells, mediating immune rejection of corneal grafts. Applying a murine model of corneal transplantation, we aimed to investigate these CAMs expression in corneal graft rejection, and assess their role in corneal cDC trafficking.
Corneal buttons from 8-10 week old male C57BL/6 mice were sutured onto age- and sex-matched BALB/c mice. Accepted and rejected corneas were harvested and the gene and protein expression of CAMs assessed by real-time PCR and immunohistochemistry, respectively. Furthermore, in vivo rolling and adhesion of adoptively transferred fluorescently-labeled cDCs were studied in limbal vessels utilizing epi-fluorescent intravital microscope. Graft rejectors received either 100µg of MAdCAM-1 blocking antibody or isotype control via tail vein. Then, 20 million labeled cDCs were injected through a cannula into the contralateral carotid artery and visualized in the corneolimbal vessels of the transplanted eye. As an internal control cDC rolling and sticking in naïve mice compared to rejectors.
MAdCAM-1 and VCAM-1 mRNA were significantly increased in corneas of rejected grafts as compared to accepted grafts (8 and 3.2 fold) and naïve corneas (4.5 and 6.4 fold), respectively (p<0.05). Immunohistochemistry of whole-mounted corneas confirmed the expression of MAdCAM-1 and VCAM-1 on corneal blood and surprisingly on lymphatic vessels. Intravital microscopy demonstrated a significant increase in rolling and sticking fraction of adoptively transferred cDCs in rejectors compared with naïve mice. Interestingly, following MAdCAM-1 blockade we observed significant decreased rolling and sticking fractions (10% and 0.5%) as compared with isotype control (14% and 3%), respectively. (p<0.05).
We demonstrate, for the first time, upregulation of MAdCAM-1 and VCAM-1 also their expression on both blood and lymphatic vessels in rejected corneal transplants. MAdCAM-1 mediates corneal cDC trafficking in rejected grafts through reduction of rolling and sticking. MAdCAM-1 or its receptors may provide new molecular targets for pharmacological intervention to enhance corneal allograft survival.
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